tbuckley/cabot-search huggingface dataset:
Prostate cancer screening: Have we tipped the seesaw?
Authors: Matthew David Hobbs, Natalia Norori, Thomas Harding, Amy Rylance
Journal: Journal of Clinical Oncology (2023)

43 Background: Screening for prostate cancer has been and remains contentious with evidence of harms and benefits finely balanced and inadequate to tip the see saw one way or another in order to give men clear, understandable guidance on PSA testing. In recent years the diagnostic pathway has changed significantly delivering a modern pathway that is likely to do far less harm and possibly more benefit. Our work quantifies the levels of harm and benefit at each stage of the entire pathway currently used in the UK from initial PSA through to biopsy-confirmed diagnosis of prostate cancer. Methods: Combining the full results of the most recent high quality diagnosis clinical trials, as well as real world evidence and practice patterns we have mapped each stage of the UK diagnostic pathway. Through this research we are able to quantify the number of men benefitting (i.e. those who move through the pathway correctly with an eventual diagnosis of clinically significant prostate cancer) and the number of men suffering harm (those who suffer biopsy side effects or who are subjected to unnecessary testing as they move through the pathway with no clinically significant cancer). Results: Initial results using clinical trial data and current practice patterns in the UK indicate that 10,000 men entering the diagnostic pathway with a PSA test would generate the following results. Diagnostic outcomes: 463 men would be diagnosed with a clinically significant (Gleason 3+4 or above) localised prostate cancer; 110 men would be diagnosed with a clinically insignificant (Gleason 3+3) prostate cancer; and 646 men would be taken through the entire diagnostic pathway with no diagnosis of prostate cancer. Harm: a maximum of 38 men would suffer clinical side effects from their biopsy. Healthcare costs: 10,000 PSA tests, 1,449 multiparametric MRI scans, and 1,207 biopsies would yield 463 significant cancers diagnosed. An estimated 1,258 clinically insignificant and 168 clinically significant cancers would remain undiagnosed using the current diagnostic pathway due to initial PSA below 3ng/ml. Conclusions: Rates of biopsy-related harm in modern practice are encouragingly low and likely to reduce further. A PSA-initiated diagnostic pathway misses a significant proportion of clinically important cancers. It is interesting to note the high conversion from MRI to biopsy in the data underpinning this model. Next steps will include analysis of the same outcomes in several centres in the UK to determine if actual practice matches expected outcomes (harms and benefits) from previous clinical trials.
Association of peripheral blood neutrophil-lymphocyte ratio (NLR) and red cell distribution width (RDW) with immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (mUC).
Authors: Talal El Zarif, Jonathan Thomas, Irbaz Bin Riaz, Dory Freeman, Ilana Epstein, Pier Vitale Nuzzo, Matthew Davidsohn, Heather McClure, Ayah Matar, Uttam Kalluri, Ritu Yadav, Charlene Mantia, Praful Ravi, Bradley Alexander McGregor, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2023)

540 Background: Determining a benefit from ICIs radiographically may take months and may be confounded by pseudoprogression. The NLR &amp; RDW are readily accessible inflammatory markers from routine peripheral blood analysis and have been associated with outcomes in malignancies. We evaluated the association of early changes in NLR and RDW within 4 weeks after initiating ICI with any regression of tumor (ART) and overall survival (OS) in mUC. Methods: This study included de-identified data from Dana-Farber Cancer Institute in pts with mUC who were treated with ICIs from 2015 to 2020. Age, gender, setting (untreated vs. post-platinum), sites of metastasis (mets), performance status (PS), platelet count, RDW, and NLR at baseline and 3-4 weeks after initiating the ICI were collected. The primary objective was to assess the association of early increase in NLR by ≥1.0 from baseline or RDW at 3-4 weeks (as a continuous variable) post-ICI therapy with ART and OS. ART was assessed via subsequent imaging at any time point while on ICI. A multivariable logistic regression model and Cox proportional-hazards model were employed to identify the association of NLR changes with ART and OS, respectively, using backward selection. Results: A total of 330 pts were evaluable. The median age was 70 years, 72.1% (n = 298) were male and 69.4% (n= 227) received post-platinum ICI (remaining were platinum naïve). 46.5% (n = 146) experienced ART and the median OS was 13 months (11.14-16.14). An increase in NLR ≥ 1 in 3-4 weeks was associated with a lower rate of ART (OR: 0.41, 95% CI 0.24-0.70; p: 0.001) and worse OS (hazard ratio [HR]: 1.84, 95% CI 1.37-2.46; p &lt; 0.0001) on multivariable analysis (Table). Higher RDW values at 3-4 weeks were associated with worse OS (HR: 1.08, 95% CI 1.03-1.14; p: 0.0004) but were not associated with ART. Conclusions: In pts with mUC initiating ICI, an early increase in NLR ≥ 1 and higher RDW in 3-4 weeks were associated with poor outcomes. Early changes in these readily available variables may enable early modification or intensification of therapy to improve outcomes. External validation of these findings is warranted. [Table: see text]
Origin of extragonadal versus gonadal seminomas.
Authors: Sara Tasneem, Jim Zhongning Chen, Andrew Johns, Shi-Ming Tu, Marcos Roberto Estecio
Journal: Journal of Clinical Oncology (2023)

423 Background: There is debate whether a primary seminoma of the anterior mediastinum originates from a stranded germ cell in the midline near the thymus as it migrates from the yolk sac to the gonad 1 or from abnormal development of the thymic anlage during embryogenesis. 2 We hypothesized that if extragonadal seminoma were to arise from an adult stem cell at an ectopic site rather than from an errant primordial germ cell (PGC), it would display a methylated imprint resembling that of thymic epithelial tumors, such as a thymoma, rather than that of a gonadal seminoma. Methods: We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA of testicular seminoma, anterior mediastinal seminoma, thymomas, atypical thymomas, and thymic carcinomas. Results: RRBS of testicular seminoma (n=1), anterior mediastinal seminoma (n=1), thymomas (n=2), atypical thymomas (n=2), and thymic carcinomas (n=2) showed that the methylated genetic imprint of an extragonadal seminoma clustered more closely to that of an atypical thymoma than that of testicular seminoma. Conclusions: Our preliminary RRBS results suggest that extragonadal seminoma may have a thymic rather than PGC origin. We plan to confirm these results by evaluating certain PGC-specific genetic biomarkers and epigenetic signatures in additional cases. References: 1. Dixon FJ, Moore RA. Testicular tumors: a clinicopathological study. Cancer 1953;6:427. 2. Schlumberger HG. Teratoma of the anterior mediastinum in the group of military age: a study of sixteen cases, and a review of theories of genesis. Arch Pathol 1946;41:398.
Non-communicable diseases, injuries, and mental ill-health in Africa: the role of the Africa Centres for Disease Control and Prevention
Authors: Abdulaziz Mohammed, Nina Putnis, Adelard Kakunze, Sarah Payne Riches, Emily Humphreys, Julian Eaton, Tazeem Bhatia, Osman Dar, Tajudeen Raji, Ian F Walker, Ahmed Ogwell
Journal: The Lancet Global Health (2023)
Estimating national-level measles case–fatality ratios in low-income and middle-income countries: an updated systematic review and modelling study
Authors: Alyssa N Sbarra, Jonathan F Mosser, Mark Jit, Matthew Ferrari, Rebecca E Ramshaw, Patrick O'Connor, L Kendall Krause, Emma L B Rogowski, Allison Portnoy
Journal: The Lancet Global Health (2023)
Microenvironment responsive nanocomposite hydrogel with NIR photothermal therapy, vascularization and anti-inflammation for diabetic infected wound healing
Authors: Shuangli Zhu, Bangjiao Zhao, Maocai Li, Hao Wang, Jiayi Zhu, Qingtao Li, Huichang Gao, Qi Feng, Xiaodong Cao
Journal: Bioactive Materials (2023)

Bacterial infection, excessive inflammation and damaging blood vessels network are the major factors to delay the healing of diabetic ulcer. At present, most of wound repair materials are passive and can't response to the wound microenvironment, resulting in a low utilization of bioactive substances and hence a poor therapeutic effect. Therefore, it's essential to design an intelligent wound dressing responsive to the wound microenvironment to achieve the release of drugs on-demand on the basis of multifunctionality. In this work, metformin-laden CuPDA NPs composite hydrogel (Met@ CuPDA NPs/HG) was fabricated by dynamic phenylborate bonding of gelatin modified by dopamine (Gel-DA), Cu-loaded polydopamine nanoparticles (CuPDA NPs) with hyaluronic acid modified by phenyl boronate acid (HA-PBA), which possessed good injectability, self-healing, adhesive and DPPH scavenging performance. The slow release of metformin was achieved by the interaction with CuPDA NPs, boric groups (B-N coordination) and the constraint of hydrogel network. Metformin had a pH and glucose responsive release behavior to treat different wound microenvironment intelligently. Moreover, CuPDA NPs endowed the hydrogel excellent photothermal responsiveness to kill bacteria of >95% within 10 min and also the slow release of Cu2+ to protect wound from infection for a long time. Met@ CuPDA NPs/HG also recruited cells to a certain direction and promoted vascularization by releasing Cu2+. More importantly, Met@CuPDA NPs/HG effectively decreased the inflammation by eliminating ROS and inhibiting the activation of NF-κB pathway. Animal experiments demonstrated that Met@CuPDA NPs/HG significantly promoted wound healing of diabetic SD rats by killing bacteria, inhibiting inflammation, improving angiogenesis and accelerating the deposition of ECM and collagen. Therefore, Met@CuPDA NPs/HG had a great application potential for diabetic wound healing.
The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study
Authors: Rebecca A Clark, Christinah Mukandavire, Allison Portnoy, Chathika K Weerasuriya, Arminder Deol, Danny Scarponi, Andrew Iskauskas, Roel Bakker, Matthew Quaife, Shelly Malhotra, Nebiat Gebreselassie, Matteo Zignol, Raymond C W Hutubessy, Birgitte Giersing, Mark Jit, Rebecca C Harris, Nicolas A Menzies, Richard G White
Journal: The Lancet Global Health (2023)

BackgroundTuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios.MethodsWe calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy.FindingsThe base-case scenario would prevent 44·0 million (95% uncertainty range 37·2–51·6) tuberculosis cases and 5·0 million (4·6–5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6–76·0) cases and 7·9 million (7·3–8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6–10·1) cases and 1·1 million (0·9–1·2) deaths before 2050, relative to baseline.InterpretationOur results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction—at a pace similar to that seen for COVID-19 vaccines—would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up.FundingWHO (2020/985800-0).TranslationsFor the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section.
How Instructions, Learning, and Expectations Shape Pain and Neurobiological Responses
Authors: Lauren Y. Atlas
Journal: Annual Review of Neuroscience (2023)

Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.
Neural Circuits for Emotion
Authors: Meryl Malezieux, Alexandra S. Klein, Nadine Gogolla
Journal: Annual Review of Neuroscience (2023)

Emotions are fundamental to our experience and behavior, affecting and motivating all aspects of our lives. Scientists of various disciplines have been fascinated by emotions for centuries, yet even today vigorous debates abound about how to define emotions and how to best study their neural underpinnings. Defining emotions from an evolutionary perspective and acknowledging their important functional roles in supporting survival allows the study of emotion states in diverse species. This approach enables taking advantage of modern tools in behavioral, systems, and circuit neurosciences, allowing the precise dissection of neural mechanisms and behavior underlying emotion processes in model organisms. Here we review findings about the neural circuit mechanisms underlying emotion processing across species and try to identify points of convergence as well as important next steps in the pursuit of understanding how emotions emerge from neural activity.
Diaphragm Neurostimulation Assisted Ventilation in Critically Ill Patients
Authors: Harry Etienne, Idunn S. Morris, Greet Hermans, Leo Heunks, Ewan C. Goligher, Samir Jaber, Capucine Morelot-Panzini, Jalal Assouad, Jésus Gonzalez-Bermejo, Laurent Papazian, Thomas Similowski, Alexandre Demoule, Martin Dres
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Diaphragm neurostimulation consists of placing electrodes directly on or in proximity to the phrenic nerve(s) to elicit diaphragmatic contractions. Since its initial description in the 18th century, indications have shifted from cardiopulmonary resuscitation to long-term ventilatory support. Recently, the technical development of devices for temporary diaphragm neurostimulation has opened up the possibility of a new era for the management of mechanically ventilated patients. Combining positive pressure ventilation with diaphragm neurostimulation offers a potentially promising new approach to the delivery of mechanical ventilation which may benefit multiple organ systems. Maintaining diaphragm contractions during ventilation may attenuate diaphragm atrophy and accelerate weaning from mechanical ventilation. Preventing atelectasis and preserving lung volume can reduce lung stress and strain and improve homogeneity of ventilation, potentially mitigating ventilator-induced lung injury. Furthermore, restoring the thoracoabdominal pressure gradient generated by diaphragm contractions may attenuate the drop in cardiac output induced by positive pressure ventilation. Experimental evidence suggests diaphragm neurostimulation may prevent neuroinflammation associated with mechanical ventilation. This review describes the historical development and evolving approaches to diaphragm neurostimulation during mechanical ventilation and surveys the potential mechanisms of benefit. The review proposes a research agenda and offers perspectives for the future of diaphragm neurostimulation assisted mechanical ventilation for critically ill patients.
Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Anil P. Bidkar, Sinan Wang, Kondapa Naidu Bobba, Emily Chan, Scott Bidlingmaier, Emily A. Egusa, Robin Peter, Umama Ali, Niranjan Meher, Anju Wadhwa, Suchi Dhrona, Chandrashekhar Dasari, Denis Beckford-Vera, Yang Su, Ryan Tang, Li Zhang, Jiang He, David M. Wilson, Rahul Aggarwal, Henry F. VanBrocklin, Youngho Seo, Jonathan Chou, Bin Liu, Robert R. Flavell
Journal: Clinical Cancer Research (2023)

Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody.
SARS-CoV-2 variants resistant to monoclonal antibodies in immunocompromised patients constitute a public health concern
Authors: Arturo Casadevall, Daniele Focosi
Journal: Journal of Clinical Investigation (2023)

COVID-19 in immunocompromised hosts has emerged as a difficult therapeutic management problem. Immunocompromised hosts mount weak responses to SARS-CoV-2 and manifest infection outcomes ranging from severe disease to persistent infection. Weakened immune systems mean greater viral loads and increased opportunities for viral evolution. Gupta, Konnova, et al. report the emergence of resistant SARS-CoV-2 variants in immunocompromised patients after monoclonal antibody (mAb) therapy. mAbs target only a single determinant in the viral Spike protein, which is a weakness of such therapy when treating a mutagenic and variable virus. Hence, the emergence of mAb resistance could have been anticipated, but its documentation is important because it has major public health implications, since such resistant variants have the potential to spread and escape vaccine immunity. For immunocompromised patients, these findings suggest the need for combination therapy with antiviral drugs and the use of polyclonal antibody preparations such as convalescent plasma.
HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation
Authors: Lionel Chia, Bowen Wang, Jung-Hyun Kim, Li Z. Luo, Shuai Shuai, Iliana Herrera, Sophia Y. Chen, Liping Li, Lingling Xian, Tait Huso, Mohammad Heydarian, Karen Reddy, Woo Jung Sung, Shun Ishiyama, Gongbo Guo, Elizabeth Jaffee, Lei Zheng, Leslie M. Cope, Kathy Gabrielson, Laura Wood, Linda Resar
Journal: Journal of Clinical Investigation (2023)

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.
The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response
Authors: Yi-Rong Zeng, Jun-Bin Song, Dezheng Wang, Zi-Xuan Huang, Cheng Zhang, Yi-Ping Sun, Gang Shu, Yue Xiong, Kun-Liang Guan, Dan Ye, Pu Wang
Journal: Journal of Clinical Investigation (2023)

Pathogens and inflammatory conditions rapidly induce the expression of immune-responsive gene 1 (IRG1) in cells of myeloid lineage. IRG1 encodes an aconitate decarboxylase (ACOD1) that produces the immunomodulatory metabolite itaconate (ITA). In addition to rapid intracellular accumulation, ITA is also secreted from the cell, but whether secreted ITA functions as a signaling molecule is unclear. Here, we identified ITA as an orthosteric agonist of the GPCR OXGR1, with an EC50 of approximately 0.3 mM, which was in the same range as the physiological concentration of extracellular ITA upon macrophage activation. ITA activated OXGR1 to induce Ca2+ mobilization, ERK phosphorylation, and endocytosis of the receptor. In a mouse model of pulmonary infection with bacterial Pseudomonas aeruginosa, ITA stimulated Oxgr1-dependent mucus secretion and transport in respiratory epithelium, the primary innate defense mechanism of the airway. Our study thus identifies ITA as a bona fide ligand for OXGR1 and the ITA/OXGR1 paracrine signaling pathway during the pulmonary innate immune response.
Connexin hemichannels as candidate targets for cardioprotective and anti-arrhythmic treatments
Authors: Luc Leybaert, Maarten A.J. De Smet, Alessio Lissoni, Rosalie Allewaert, H. Llewelyn Roderick, Geert Bultynck, Mario Delmar, Karin R. Sipido, Katja Witschas
Journal: Journal of Clinical Investigation (2023)

Connexins are crucial cardiac proteins that form hemichannels and gap junctions. Gap junctions are responsible for the propagation of electrical and chemical signals between myocardial cells and cells of the specialized conduction system in order to synchronize the cardiac cycle and steer cardiac pump function. Gap junctions are normally open, while hemichannels are closed, but pathological circumstances may close gap junctions and open hemichannels, thereby perturbing cardiac function and homeostasis. Current evidence demonstrates an emerging role of hemichannels in myocardial ischemia and arrhythmia, and tools are now available to selectively inhibit hemichannels without inhibiting gap junctions as well as to stimulate hemichannel incorporation into gap junctions. We review available experimental evidence for hemichannel contributions to cellular pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these to insights at the level of molecular control of connexin-43-based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be key for further research and development of new connexin-based experimental approaches for treating heart disease.